Paper type: Conceptual perspective. Background(s): Physics, biology, epistemology Perspectives: Theory of autopoietic systems, Popperian evolutionary epistemology and the biology of cognition. Context: This paper is a contribution to developing the theories of hierarchically complex living systems and the natures of knowledge in such systems. Problem: Dissonance between the literatures of knowledge management and organization theory and my observations of the living organization led to consideration of foundation questions: What does it mean to be alive? What is knowledge? How are life (...) and knowledge related? Method: The approach is synthetic and multidisciplinary. The concept of autopoiesis (as defined by Maturana) as a definition for life, and knowledge as a product of autopoiesis are developed from first principles regarding the behavior of dynamical systems in time. Results: Autopoiesis and the construction of knowledge are inseparable aspects of physical phenomena scalable to many levels of organization (e.g., cells, multicellular organisms, organizations, social systems, etc.). The result unifies theories of epistemology, physical dynamics, life, biological evolution, knowledge and social systems. Implications: Results highlight the importance to understand autopoiesis as first defined by Maturana and Varela – as a complex physical phenomenon persisting over time. Autopoietic “self-observation” is not paradoxical. As dynamic physical processes, any internal/external activities relating to “observations” are displaced in time. The worlds living systems act on are not those observed. “Circularly closed” systems are actually open spirals along the axis of time. (shrink)